PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65

Missense mutations in PTEN-induced kinase 1 (PINK1) cause autosomal-recessive inherited Parkinson's disease (PD). We have exploited our recent discovery that recombinant insect PINK1 is catalytically active to test whether PINK1 directly phosphorylates 15 proteins encoded by PD-associated genes...

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Vydané v:	Open biology Ročník 2; číslo 5; s. 120080
Hlavní autori:	Kondapalli, Chandana, Kazlauskaite, Agne, Zhang, Ning, Woodroof, Helen I., Campbell, David G., Gourlay, Robert, Burchell, Lynn, Walden, Helen, Macartney, Thomas J., Deak, Maria, Knebel, Axel, Alessi, Dario R., Muqit, Miratul M. K.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England The Royal Society 01.05.2012
Predmet:	Animals Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology Enzyme Activation - drug effects HEK293 Cells Humans Insect Proteins - genetics Insect Proteins - physiology Membrane Potential, Mitochondrial - physiology Parkin Parkinson Disease - metabolism Parkinson's Disease Phosphorylation - drug effects Phosphoserine - metabolism Phosphothreonine - metabolism PINK1 Protein Kinases - genetics Protein Kinases - physiology Protein Processing, Post-Translational - drug effects Protein Stability - drug effects Protein Structure, Tertiary Receptor-Like Protein Tyrosine Phosphatases, Class 2 - pharmacology Recombinant Fusion Proteins - physiology RNA Interference RNA, Small Interfering - pharmacology Tribolium - enzymology Tribolium - genetics Ubiquitin-Protein Ligases - metabolism PINK1 Parkinson's disease Parkin
ISSN:	2046-2441, 2046-2441
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Shrnutí:	Missense mutations in PTEN-induced kinase 1 (PINK1) cause autosomal-recessive inherited Parkinson's disease (PD). We have exploited our recent discovery that recombinant insect PINK1 is catalytically active to test whether PINK1 directly phosphorylates 15 proteins encoded by PD-associated genes as well as proteins reported to bind PINK1. We have discovered that insect PINK1 efficiently phosphorylates only one of these proteins, namely the E3 ligase Parkin. We have mapped the phosphorylation site to a highly conserved residue within the Ubl domain of Parkin at Ser65. We show that human PINK1 is specifically activated by mitochondrial membrane potential (Δψm) depolarization, enabling it to phosphorylate Parkin at Ser65. We further show that phosphorylation of Parkin at Ser65 leads to marked activation of its E3 ligase activity that is prevented by mutation of Ser65 or inactivation of PINK1. We provide evidence that once activated, PINK1 autophosphorylates at several residues, including Thr257, which is accompanied by an electrophoretic mobility band-shift. These results provide the first evidence that PINK1 is activated following Δψm depolarization and suggest that PINK1 directly phosphorylates and activates Parkin. Our findings indicate that monitoring phosphorylation of Parkin at Ser65 and/or PINK1 at Thr257 represent the first biomarkers for examining activity of the PINK1-Parkin signalling pathway in vivo. Our findings also suggest that small molecule activators of Parkin that mimic the effect of PINK1 phosphorylation may confer therapeutic benefit for PD.
Bibliografia:	istex:FC7FB588B912041A8A84A849453922690B0C7D55 ark:/67375/V84-VC2ZH7ZC-S href:rsob120080.pdf ArticleID:rsob120080 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2046-2441 2046-2441
DOI:	10.1098/rsob.120080